1. Field of the Invention
The present invention relates to novel anti-inflammatory and antiallergic compounds of the glucocorticosteroid series. The present invention also relates to methods of preparing such a compound, pharmaceutical compositions which contain such a compound, combinations which contain such a compound and therapeutic uses of such a compound.
2. Discussion of the Background
Corticosteroids are potent anti-inflammatory agents, able to decrease the number, activity, and movement of inflammatory cells. They are commonly used to treat a wide range of chronic and acute inflammatory conditions including asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, rheumatoid arthritis, inflammatory bowel disease and autoimmune diseases.
Corticosteroids mediate their effects through the glucocorticoid receptor (GR). The binding of corticosteroids to GR induces its nuclear translocation which, in turn, affects a number of downstream pathways via DNA-binding-dependent (e.g. transactivation) and -independent (e.g. transespression) mechanisms.
Corticosteroids for treating chronic inflammatory conditions in the lung such as asthma and COPD are currently administered through inhalation. One of the advantages of employing inhaled corticosteroids (ICS) is the possibility of delivering the drug directly at the site of action, limiting systemic side-effects, thus resulting in a more rapid clinical response and a higher therapeutic ratio.
Although ICS treatment can afford important benefits, especially in asthma it is important to minimise ICS systemic exposure which leads to the occurrence and severity of unwanted side effects that may be associated with chronic administration. Moreover, the limited duration of action of ICS currently available in the clinical practice contributes to suboptimal management of the disease. While the inhaler technology is the key point to target the lung, the modulation of the substituents on the corticosteroids molecular scaffold is important for the optimization of pharmacokinetic and pharmacodynamic properties in order to decrease oral bioavailability, confine pharmacological activity only in the lung (prodrugs and soft drugs) and increase systemic clearance. Moreover, long lasting ICS activity in the lung is highly desirable as once daily administration of ICS would allow the reduction of the frequency of administration and, thus, substantially improve patient compliance and, as a result, disease management and control. In sum, there is a pressing medical need for developing ICS with improved pharmacokinetic and pharmacodynamic characteristics.
Glucocorticoid isoxazolidine derivatives are described in WO2006/005611, GB1578446, and in “Synthesis and topical anti-inflammatory activity of some steroidal [16α,17α-d] isoxazolidines” (J. Med. Chem., vol. 25, pp. 1492-1495, 1982).